Cheryl Elizabeth Rockwell
Michigan State University
Project start date: 2012-01-16
Project end date: 2014-12-31
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to Cheryl Elizabeth Rockwell
ROLE OF NRF2 IN IMMUNOTOXICITY BY FOOD ADDITIVES AND ENVIRONMENTAL CONTAMINANTS
Cheryl Elizabeth Rockwell, Postdoctoral Fellow
University Of Kansas Medical Center, Msn 1039, Kansas City, Ks 66160
Grant 1K99ES018885-01 from National Institute Of Environmental Health Sciences
Abstract: Recent studies demonstrate that nuclear factor erythroid 2-related factor 2 (Nrf2) plays a critical cytoprotective role in countering oxidative and electrophilic cellular stresses. Nrf2 is activated by a variety of chemicals, including environmental contaminants such as arsenic, cadmium, nickel, cigarette smoke, and diesel exhaust, as well as industrial byproducts, such as tetrafluoroethylcysteine. In addition, several widely used food preservatives also strongly activate Nrf2. Thus, Nrf2 activators are widely disseminated in the environment and in our food. Several papers have recently been published describing the suppressive effects of Nrf2 in innate immunity. In addition, the development of lupus-like pathology in Nrf2-null mice suggests that Nrf2 also plays an important role in adaptive immunity, but no studies examining the role of Nrf2 in lymphocytes have been published to date. Preliminary data demonstrate that activated Nrf2 inhibits IFN gamma production in activated T cells. Because IFN gamma is a key activator of macrophages and T cells, IFN gamma is considered a vital cytokine for cell-mediated adaptive immune responses (such as a response to a bacterial pathogen). The purpose of the studies proposed in this application is to determine the mechanism by which Nrf2 inhibits IFN gamma production in T cells. This will be accomplished by 1) determining the mechanism by which activation of Nrf2 inhibits IFN gamma transcription 2) determining the mechanism by which tBHQ, a Nrf2 activator, impairs immune responses in vivo and 3) determining the effect of polymorphisms and other variations in the human Keap1 gene (Nrf2 repressor) on T cell function. Because numerous environmental contaminants, industrial byproducts, and commonly used synthetic food preservatives have been shown to activate Nrf2, the effects of Nrf2 activation on different organ systems needs to be fully characterized. This is particularly pertinent for the immune system in which the effects of Nrf2 on adaptive immunity are largely uncharacterized. Moreover, the long-term and/or cumulative exposure of numerous Nrf2 activators should also be considered. The overall purpose of these studies is to determine the mechanism by which Nrf2 impairs T cell function in order to better predict the effects of acute and long-term exposure to Nrf2 activators on the immune system in humans. Several food preservatives (tBHQ, BHA, etc.) and environmental contaminants (cadmium, arsenic, etc.) activate Nrf2, a protein found in most cell types. Preliminary studies demonstrate that activation of Nrf2 has a negative impact on T cell function which leads to impaired immune responses. The proposed studies will examine how this occurs in order to better predict the impact of Nrf2 activators on the immune system
Keywords: 2-(1, 1-dimethylethyl)-1, 4-benzenediol; 2-tert-butylhydroqui; 2-tertiary-butylhydroqui; AP-1; AP-1 Enhancer-Binding Protein; AP1; AP1 protein; ATGN; Activator Protein-1; Acute; Affect; Antibody Formation; Antibody Production; Antibody Response; Antigens; Arsenic; Autoregulation; Blood erythrocyte; Blood normocyte; Cadmium; Cd element; Cell Communication and Signaling; Cell Function; Cell Nucleus; Cell Process; Cell Signaling; Cell physiology; Cells; Cellular Function; Cellular Physiology; Cellular Process; Cellular Stress; Chemicals; Computer Systems Development; Cytokine Activation; Data; Development; Development, Computer Systems; Diesel Exhaust; Drug Metabolic Detoxication; Enhancer-Binding Protein AP1; Environment; Environmental Pollution; Enzymes; Erythrocytes; Erythrocytic; Exhaust, Diesel; Exposure to; FOS gene; Food; Food Additives; Food Preservatives; Future; G0S7; Gamma interferon; Gene Expression; Gene Transcription; Gene variant; Genes; Genetic Alteration; Genetic Change; Genetic Diversity; Genetic Polymorphism; Genetic Transcription; Genetic Variation; Genetic defect; Glutathione; Glycine, N-(N-L-gamma-glutamyl-L-cysteinyl)-; Goals; Grippe; Homeostasis; Human; Human, General; IFN; IFN-Gamma; IFN-g; IFNG; INFLM; Immune; Immune Function, Cellular; Immune response; Immune system; Immunity; Immunity, Innate; Immunity, Native; Immunity, Natural; Immunity, Non-Specific; Immunoglobulin Enhancer-Binding Protein; Immunosuppression Effect; Immunosuppressions (Physiology); Immunosuppressive Effect; Individual; Inflammation; Influenza; Interferon Activation; Interferon Gamma; Interferon Suppression; Interferon Type II; Interferon gamma (human lymphocyte protein moiety reduced); Interferon, Immune; Interferon-gamma; Interferons; Intracellular Communication and Signaling; Knockout Mice; Lead; Lymphocyte; Lymphocytic; MTBHQ; Mammals, Mice; Man (Taxonomy); Man, Modern; Marrow erythrocyte; Mediating; Metabolic Detoxication, Drug; Metabolic Detoxification, Drug; Metabolic Drug Detoxications; Metabolism of Toxic Agents; Mice; Mice, Knock-out; Mice, Knockout; Molecular; Murine; Mus; Mutation; NF-E2 protein; NF-E2 transcription factor; NF-kB; NF-kappa B; NF-kappaB; NFE2 protein; NFKB; Natural Immunity; Natural immunosuppression; Ni element; Nickel; Nuclear Factor kappa B; Nuclear Transcription Factor NF-kB; Nuclear Translocation; Nucleus; Null Mouse; Organ System; Ovis; PPAR; Paper; Pathology; Pathway interactions; Pb element; Peroxisome Proliferator-Activated Receptors; Phosphatases; Phosphohydrolases; Phosphomonoesterases; Phosphoric Monoester Hydrolases; Physiological Homeostasis; Play; Polymorphism (Genetics); Polymorphism, Genetic; Polymorphism, Single Base; Production; Proteins; Protooncogene FOS; Publishing; RNA Expression; Red Blood Cells; Red Cell; Red blood corpuscule; Red cell of marrow; Repression; Research; Reticuloendothelial System, Erythrocytes; Risk Assessment; Role; SNP; SNPs; Sheep; Signal Pathway; Signal Transduction; Signal Transduction Systems; Signaling; Single Nucleotide Polymorphism; Stress; Subcellular Process; Systems Development; T-Cells; T-Lymphocyte; TBHQ; Testing; Thymus-Dependent Lymphocytes; Transcription; Transcription Factor AP-1; Transcription Factor NF-kB; Transcription, Genetic; Tuberculosis; Ubiquitilation; Ubiquitination; Ubiquitinoylation; Variant; Variation; Variation (Genetics); Viral; Work; Xenobiotics; allelic variant; antibody biosynthesis; base; biological signal transduction; blood corpuscles; body system; body system, allergic/immunologic; c fos; c-fos Gene; c-fos Proto-Oncogenes; cell type; cigarette smoke; cytokine; detoxification; disseminated TB; disseminated tuberculosis; environmental contaminant; environmental contamination; flu infection; gamma-L-Glu-L-Cys-Gly; gamma-L-Glutamyl-L-Cysteinylglycine; gene product; genome mutation; heavy metal Pb; heavy metal lead; host response; immune function; immunogen; immunoglobulin biosynthesis; immunoresponse; immunosuppression; immunotoxicity; in vivo; influenza infection; kappa B Enhancer Binding Protein; lFN-Gamma; lupus-like; lymph cell; macrophage; mono-tert-butylhydroqui; monotertiary butyl hydroqui; novel; nuclear factor kappa beta; nuclear factor-erythroid 2; organ system, allergic/immunologic; p65; pathogen; pathway; polymorphism; prevent; preventing; public health relevance; response; sensor; smoke of cigarettes; social role; systems research; tert-butylhydroqui; thymus derived lymphocyte; toxic reaction in immunology; transcription factor; tuberculous spondyloarthropathy; ubiquination; ubiquitin conjugation; v-FOS FBJ Murine Osteosarcoma Viral Oncogene Homolog
Relevance: Several food preservatives (tBHQ, BHA, etc.) and environmental contaminants (cadmium, arsenic, etc.) activate Nrf2, a protein found in most cell types. Our preliminary studies demonstrate that activation of Nrf2 has a negative impact on T cell function which leads to impaired immune responses. The proposed studies will examine how this occurs in order to better predict the impact of Nrf2 activators on the immune system
Project start date: 2010-05-01
Project end date: 2012-04-30
Budget start date: 1-MAY-2010
Budget end date: 30-APR-2011
PFA/PA: PA-09-036
1K99ES018885-01 (2010): $87209